NZ534359A - Novel amino acid derivatives, method for production thereof and pharmaceutical compositions comprising said derivative - Google Patents

Novel amino acid derivatives, method for production thereof and pharmaceutical compositions comprising said derivative

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Publication number
NZ534359A
NZ534359A NZ534359A NZ53435903A NZ534359A NZ 534359 A NZ534359 A NZ 534359A NZ 534359 A NZ534359 A NZ 534359A NZ 53435903 A NZ53435903 A NZ 53435903A NZ 534359 A NZ534359 A NZ 534359A
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New Zealand
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amino
formula
group
branched
linear
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NZ534359A
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Nanteuil Guillaume De
Philippe Gloanec
Tony Verbeuren
Alain Rupin
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Servier Lab
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Publication of NZ534359A publication Critical patent/NZ534359A/en

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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/26—Sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
    • C07C257/18—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/12—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines
    • C07C259/18—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines having carbon atoms of hydroxamidine groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/10—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of a saturated carbon skeleton containing rings
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/12—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
    • C07C311/13—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings the carbon skeleton containing six-membered aromatic rings
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/32—Sulfur atoms
    • C07D213/34—Sulfur atoms to which a second hetero atom is attached
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    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
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    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
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    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/14—Benz[f]indenes; Hydrogenated benz[f]indenes
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
    • C07C2603/28—Phenalenes; Hydrogenated phenalenes

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
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  • Diabetes (AREA)
  • Hematology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

Compounds of formula (I) are disclosed. Processes for the preparation of these compounds are also disclosed. Pharmaceutical compositions comprising these compounds are useful as a medicament in the treatment of any pathological condition involving activated protein C. These pharmaceutical compositions are also useful as a medicament in the treatment of disorders involving all haemorrhagic clinical situations such as von Willebrand's disease or haemophilia A or B and for use as an antidote medicament in antithrombotic treatments such as anticoagulant, antiplatelet and fibrinolytic treatments.

Description

New Zealand Paient Spedficaiion for Paient Number 534359 534359 m NOVEL AMINO ACID DERIVATIVES, METHOD FOR PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITIONS COMPRISING SAID DERIVATIVE The present invention relates to new amino acid compounds, to a process for their 5 preparation, to pharmaceutical compositions containing them and to the use thereof as inhibitors of trypsin-related serine proteases.
One of those serine proteases, activated protein C, is the key enzyme in a powerful physiological anticoagulation process, as its natural substrates, activated factor V and activated factor VIII, are potent promoters of blood coagulation (Dahlback B, Thrombosis 10 Research 1995,77,1-43).
Direct and specific inhibition of activated protein C is an effective means of inhibiting that natural anticoagulant process and of promoting blood coagulation in haemorrhagic clinical situations and accordingly represents an extremely promising approach in the treatment of disorders involving a dysfunction of haemostasis requiring procoagulant treatment, such as 15 von Willebrand's disease or haemophilia A or B.
Peptidomimetic compounds having inhibitory activity with respect to activated protein C have already been described in the patent specification W098/22125.
It has been especially valuable to synthesise new serine protease inhibitors in order to increase the potency and selectivity of the compounds already described in the literature.
Moreover, in the presence of traces of tissue factor and thrombomodulin, these new compounds increase the generation of thrombin in human plasma and they are active via the oral route.
INTELLECTUAL PROPERTY OFFICE Of N.Z. 2 0 sep 2005 received More specifically, the present invention relates to compounds of formula (I): wherein: Ri represents an aryl group, a heteroaryl group or a linear or branched (Ci-C6)alkyl group optionally substituted by one or more identical or different groups selected from aryl and heteroaryl, or Ri represents a group of formula -(CO)-CR6R7NR8R9 wherein : - R<5 represents a hydrogen atom or a group selected from aryl, heteroaryl, heterocycloalkyl, (C3-C8)cycloalkyl and linear or branched (Ci-C6)alkyl optionally substituted by one or more identical or different groups selected from aryl, heteroaryl, heterocycloalkyl, (C3-Cg)cycloalkyl and carboxy, - R7 represents a hydrogen atom or a linear or branched (Ci-C6)alkyl group, - or R6 and R7 together form a (C3-C8)cycloalkyl group, - Rg represents a hydrogen atom or a linear or branched (Ci-C6)alkyl group, - and R9 represents a hydrogen atom or a group R9 wherein R9 represents a group selected from: • linear or branched (Ci-C6)alkyl optionally substituted by an aryl, carboxy, linear or branched (Ci-C6)alkoxy-carbonyl or carbamoyl group, • aryl, • heteroaryl, • and sulphonyl substituted by a group selected from (C3-Cg)cycloalkyl, heterocycloalkyl, aryl (optionally substituted by an aryloxy or heteroaryloxy group), and linear or branched (Ci-C6)alkyl optionally substituted by an aryl, heteroaryl, (C3-C8)cycloalkyl or heterocycloalkyl group, O R2 represents a hydrogen atom or a linear or branched (Ci-C6)alkyl group, R3 represents a hydrogen atom or a linear or branched (Ci-C6)alkyl group optionally substituted by one or more aryl groups, R4 represents a saturated or unsaturated, 7- to 15-membered bicyclic system or a linear or branched (Ci-C6)alkyl group optionally substituted by one or more aryl groups, 5 or R3 and R4, together with the carbon atom carrying them, form a saturated or unsaturated, 3- to 18-membered, mono-, bi- or tri-cyclic system optionally containing one or more hetero atoms selected from O, S and N and optionally substituted by one or more identical or different groups selected from halogen, linear or branched (Ci-C6)alkyl, linear or branched. (Ci-C6)alkoxy, hydroxy, linear or branched 10 (Ci-C6)trihaloalkyl, amino (optionally substituted by one or more linear or branched (Ci-C6)alkyl groups) and carboxy, n represents zero, 1 or 2, Ar represents an aryl or heteroaryl group, R5 represents a group selected from amino, guanidino, cyano and amidino optionally 15 substituted by a hydroxy or linear or branched (Ci-C6)alkoxy-carbonyl group, to their optical isomers, and also to addition salts thereof with a pharmaceutically acceptable acid.
Among the pharmaceutically acceptable acids there may be mentioned, without implying any limitation, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, acetic 20 acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulphonic acid, benzenesulphonic acid, camphoric acid.
A heterocycloalkyl group is understood to mean a 3- to 8-membered, saturated monocyclic group containing one, two or three hetero atoms selected from oxygen, nitrogen and sulphur, it being understood that the heterocycle may optionally be substituted by one or more identical or different groups selected from halogen, linear or branched (Ci-C6)alkyl, linear or branched (Ci-C6)alkoxy, oxo, hydroxy, linear or branched (Ci-C6)trihaloalkyl and amino (optionally substituted by one or more linear or branched (Ci-C6)alkyl groups). Preferred heterocycloalkyl groups are morpholinyl, piperazinyl or piperidyl groups.
An aryl group is understood to mean phenyl, biphenylyl or naphthyl, each of those groups being optionally substituted by one or more identical or different groups selected from halogen, linear or branched (Ci-C6)alkyl, linear or branched (Ci-C6)alkoxy, hydroxy, linear or branched (Ci-C6)trihaloalkyl, amino (optionally substituted by one or more linear or branched (Ci-C6)alkyl groups) and carboxy.
A heteroaryl group is understood to mean a monocyclic aromatic group or a bicyclic group in which at least one of the rings is aromatic, comprising from 5 to 12 members and containing one, two or three identical or different hetero atoms selected from oxygen, nitrogen and sulphur, it being understood that the heteroaryl may optionally be substituted by one or more identical or different groups selected from halogen, linear or branched 15 (Ci-C6)alkyl, hydroxy, linear or branched (Ci-C6)alkoxy, trihalomethyl and amino (optionally substituted by one or more linear or branched (Ci-C6)alkyl groups). Among the heteroaryl groups there may be mentioned, without implying any limitation, thienyl, pyridyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl and quinolyl groups.
Preferred heteroaryl groups are pyridyl (optionally substituted), benzisoxazolyl and indazolyl groups.
An advantageous aspect of the invention relates to compounds of formula (I) wherein Ri represents a group of formula -(CCty-CHReNHRp wherein R6 represents a (C3-Cg)cycloalkyl group, or-linear or branched (Ci-C6)alkyl optionally substituted by a 25 (C3-Cg)cycloalkyl group, and R9 represents a group selected from linear or branched (Ci-C6)alkyl optionally substituted by a carboxy, linear or branched (Ci-C6)alkoxy-carbonyl or carbamoyl group, and linear or branched (Ci-C6)alkylsulphonyl substituted by a (C3-Cg)cycloalkyl group.
Another advantageous aspect of the invention relates to compounds of formula (I) wherein R3 and R4, which may be the same or different, each represent a linear or branched (Ci-C6)alkyl group.
Another advantageous aspect of the invention relates to compounds of formula (I) wherein 5 R3 and R4 together form an optionally substituted indanyl group or a cyclopentapyridyl group.
Another advantageous aspect of the invention relates to compounds of formula (I) wherein n represents 1.
Another advantageous aspect of the invention relates to compounds of formula (I) wherein 10 Ar represents a phenyl group and R5 represents an amidino group optionally substituted by a hydroxy group.
Another advantageous aspect of the invention relates to compounds of formula (I) wherein Ar represents a pyridyl group substituted by a methyl group and R5 represents an amino group.
When Ri represents a group of formula -(CCO-CHR^NRgRg wherein R^, Rs and R9 are as defined for formula (I), the carbon atom carrying the substituents R6 and NRgR9 constitutes a centre of asymmetry, the configuration of which is preferably R.
Among the preferred compounds of the invention there may be mentioned more especially: - {[(1 R)-2-( {2- [({4-amidinobenzyl} -amino)-carbonyl] -indan-2-yl} -amino)-1 -cyclo- hexyl-2-oxoethyl]-amino}acetic acid, its optical isomers, and also addition salts thereof with a pharmaceutically acceptable acid, - ethyl {[(1 R)-2-( {2- [({4- [amino-(hydroxyimino)-methyl] -benzyl} -amino)-carbonyl] -indan-2-yl}-amino)-l-cyclohexyl-2-oxoethyl]-amino}acetate, its optical isomers, and 25 also addition salts thereof with a pharmaceutically acceptable acid, - {[(1 R)-2-( {2- [( { 4-amidinobenzyl} -amino)-carbonyl] -indan-2-yl} -amino)-1 -cyclo-hexylmethyl-2-oxoethyl]-amino}acetic acid, its optical isomers, and also addition salts thereof with a pharmaceutically acceptable acid, - {[(1 R)-2-( {2- [({4-amidinobenzyl} -amino)-carbonyl] -indan-2-yl} -amino)-1 -isopropyl-2-oxoethyl]-amino}acetic acid, its optical isomers, and also addition salts thereof with a pharmaceutically acceptable acid, - N-(4-amidinobenzyl)-2-[((2R)-2-cyclohexyl-2- {[(cyclohexylmethyl)-sulphonyl]-amino}-ethanoyl)-amino]-2-indancarboxamide, its optical isomers, and also addition salts thereof with a pharmaceutically acceptable acid, - N-(4-amidinobenzyl)-2-[((2R)-2-{[(cyclohexylmethyl)-sulphonyl]-amino}-3-methyl-butanoyl)-amino]-2-indancarboxamide, its optical isomers, and also addition salts thereof with a pharmaceutically acceptable acid, - N-(4-amidinobenzyl)-2-[((2R)-2-{[isobutylsulphonyl]-amino}-3-methylbutanoyl)-amino]-2-indancarboxamide, its optical isomers, and also addition salts thereof with a pharmaceutically acceptable acid, - andN-(4-amidinobenzyl)-6-[((2R)-2-{[(cyclohexylmethyl)-sulphonyl]-amino}-3-methylbutanoyl)-amino]-6,7-dihydro-5i/-cyclopenta[b]pyridine-6-carboxamide, its optical isomers, and also addition salts thereof with a pharmaceutically acceptable acid.
The invention relates also to a process for the preparation of compounds of formula (I), which process is characterised in that a compound of formula (II): wherein R3 and R4 are as defined for formula (I) and Pi represents a protecting group for the amino function, is reacted, under peptide coupling conditions, with a compound of formula (III): H2N^(CH2)n-Ar-R'5 (III), wherein n and Ar are as defined for formula (I) and R'5 represents a group selected from amino, guanidino and amidino optionally substituted by a hydroxy or linear or branched (Ci-C6)alkoxy-carbonyl group, each of those groups being optionally substituted by a protecting group, to yield, after deprotection, the compound of formula (IV): O H2N^^ttt-(ch2)„ H "-Ar R'5 (IV), r3 R4 wherein R3, R4, n, Ar and R'5 are as defined hereinbefore, which is reacted: • either, when it is desired to obtain compounds of formula (I) wherein Ri represents an 10 aryl group, a heteroaryl group or a linear or branched (Ci-C6)alkyl group which is optionally substituted, with a compound of formula (V): Ria-Z (V), wherein Ria represents an aryl group, a heteroaryl group or a linear or branched (Ci-C6)alkyl group optionally substituted by one or more groups selected from aryl 15 and heteroaryl, and Z represents a leaving group such as, for example, a halogen atom or a tosylate, mesylate or triflate group, to yield, after optional deprotection, the compounds of formula (la), a particular case of the compounds of formula (I): O R,AN^ANHXCH2)^Ar_R5 ^ R37 R4 wherein Ria, R2, R3, R4, n, Ar and R5 are as defined hereinbefore, • or, when it is desired to obtain compounds of formula (I) wherein Ri represents an optionally substituted, linear or branched (C2-C6)alkyl group, with a compound of formula (VI), under reductive amination conditions : ,» Rib-CHO (VI), wherein Rib represents a linear or branched (Ci-C5)alkyl group optionally substituted by one or more groups selected from aryl and heteroaryl, to yield, after optional deprotection, the compounds of formula (lb), a particular case of the compounds of formula (I): O R lb* ;■Nrn ;NH Ar Rs ;} / P ;(lb), ;R3 ^4 ;wherein Rib, R2, R3, R4, n, Ar and R5 are as defined hereinbefore, ;10 ;or, when it is desired to obtain compounds of formula (I) wherein Ri represents a group of formula -(CO)-CR6R7NR8R9, wherein R6, R7, Rs and R9 are as defined for formula (I), with a compound of formula (VII), under peptide coupling conditions : ;R ;P2HN ;o ;(VII), ;wherein R^ and R7 are as defined for formula (I) and P2 represents a protecting group for the amino function, to yield, after deprotection, the compound of formula (VIII) : ;O ;NH Ar R's ;/ 1? ;(VIII), ;wherein Rg, R7, R2, R3, R4, n, Ar and R'5 are as defined hereinbefore, ;15 which is reacted, if desired, with a compound of formula (IX) : ;R'9-Z (IX), ;wherein R'9 is as defined for formula (I) and Z represents a leaving group such as, for example, a halogen atom or a tosylate, mesylate or triflate group, ;to yield the compound of formula (X) : ;-9- ;*9™' J ~X "NH"(CH2)"^Ar-R'5 (X), o r{ R4 wherein R'9, R6, R7, R2, R3, R4, n, Ar and R'5 are as defined hereinbefore, which compounds of formula (VIII) or (X) are reacted, if desired, with a compound of formula (XI) : RVZ (XI), wherein R'g represents a linear or branched (Ci-C6)alkyl group and Z represents a leaving group such as, for example, a halogen atom or a tosylate, mesylate or triflate group, to yield the compound of formula (XII): O W" y (XII), o r3 r4 wherein R'g, R^, R7, R2, R3, R4, n, Ar and R'5 are as defined hereinbefore and R9 is as defined for formula (I), which compounds of formula (VIII), (X) or (XII) are optionally deprotected to yield the compound of formula (Ic), a particular case of the compounds of formula (I) : O r3 r4 wherein Rg, R9, R$, R7, R2, R3, R4, n, Ar and R5 are as defined hereinbefore, the compounds of formulae (la), (lb) and (Ic) constituting the totality of the compounds of formula (I), which are purified, if necessary, according to a conventional purification technique, are separated, if desired, into their isomers according to a conventional separation technique and are converted, if desired, into their addition salts with a 20 pharmaceutically acceptable acid.
Besides the fact that the compounds of the present invention are new, they possess especially valuable pharmacological properties.
They are powerful inhibitors of activated protein C, making them useful in the treatment of any pathological condition involving activated protein C and especially in the treatment of 5 disorders involving a dysfunction of haemostasis requiring procoagulant treatment, including all haemorrhagic clinical situations such as von Willebrand's disease or haemophilia A or B.
They may also be used as antidote medicaments in antithrombotic treatments such as anticoagulant, antiplatelet and fibrinolytic treatments.
The invention relates also to pharmaceutical compositions comprising, as active ingredient, a compound of formula (I) with one or more appropriate, inert, non-toxic excipients. Among the pharmaceutical compositions according to the invention there may be mentioned more especially those that are suitable for oral, parenteral (intravenous or subcutaneous) or nasal administration, tablets or dragees, sublingual tablets, gelatin 15 capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations, drinkable suspensions etc.
The useful dosage can be varied according to the nature and severity of the disorder, the administration route and the age and weight of the patient and ranges from 1 to 500 mg per day in one or more administrations.
The Examples that follow illustrate the invention but do not limit it in any way.
The starting materials used are products that are known or that are prepared according to known operating procedures.
Preparations A to F yield synthesis intermediates that are useful in preparing compounds of the invention.
The structures of the compounds described in the Examples were determined according to the usual spectrophotometric techniques (infrared, NMR, mass spectrometry).
PREPARATION A: Benzyl [4-aminomethyl-phenyl]-(imino)-methyl-carbamate The expected product is obtained according to the procedure described by G. De Nanteuil 5 , et al. (Synth. Comm. 1998, Vol. 28 N° 23, pp. 4419-4429).
PREPARATION B : Benzyl [4-ammomethyl-phenyl]-(hydroxyimino)-methyl- carbamate The expected product is obtained according to the procedure described by G. De Nanteuil etal. (Synth. Comm. 1998, Vol. 28 N° 23, pp. 4419-4429).
PREPARATION C : 6-Amino-3-aminomethyl-2-methyIpyridme Step A : 6-Amino-3-cyano-2-methylpyridine Copper(I) cyanide (12 mmol) is added to 10 mmol of 6-amino-3-bromo-2-methylpyridine dissolved in dimethylformamide. The mixture is refluxed for 10 hours, then cooled to 80°C and poured into a solution of sodium cyanide (40 mmol) in water. After stirring for 1 hour 15 at ambient temperature, the mixture is extracted with ethyl acetate. The organic phase is washed and then dried and evaporated to yield the expected product in the form of an ochre solid.
Step B: 6-Amino-3-aminomethyl-2-methylpyridine A solution of the compound described in the Step above (10 mmol) in ethanol is placed under hydrogen overnight in the presence of Raney nickel. After filtering off the catalyst, the solvent is evaporated off to yield the expected product.
PREPARATION D : Methyl [4-aminomethyl-phenyl]-(imino)-methyl-carbamate The expected product is obtained according to the procedure described by G. De Nanteuil et al. (Synth. Comm. 1998, Vol. 28 N° 23, pp. 4419-4429), starting from 4-bromomethyl-benzonitrile and methyl chloroformate.
PREPARATION E : Hexyl [4-aminomethyl-phenyl]-(imino)-methyI-carbamate The expected product is obtained according to the procedure described by G. De Nanteuil et al. (Synth. Comm. 1998, Vol. 28 N° 23, pp. 4419-4429), starting from 4-bromomethyl-benzonitrile and hexyl chloroformate.
PREPARATION F: 4-Aminomethyl-N-hydroxybenzenecarboximidamide The expected product is obtained according to the procedure described by G. De Nanteuil etal. (Synth. Comm. 1998, Vol. 28 N° 23, pp. 4419-4429).
EXAMPLE 1: {[(iR)-2-({2-[({4-AmidinobenzyI}-amino)-carbonyI]-indan-2-yl}-amino)-l-cyclohexy 1-2-oxo ethyl]-amino} ace tic acid hydrochloride Step A : Benzyl (4-{[({2-[(tert-butyloxycarbonyl)-amino]-indan-2-yl}-carbonyl)-amino]-methyl}-phenyl)-(imino)-methyl-carbamate To a solution of 2-[(tert-butyloxycarbonyl)-amino]-2-indancarboxylic acid (10 mmol) and the compound described-in Preparation A (10 mmol) in dimethylformamide there are added 0-( 1 //-benzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (11 mmol) and diisopropylethylamine (11 mmol). After stirring overnight at ambient temperature, the solvent is evaporated off. The residue obtained is taken up in ethyl acetate. The organic phase is washed, dried and then evaporated. The expected product is obtained after purification of the residue by chromatography on silica gel, using a mixture of dichloromethane/ethyl acetate (1/1) as eluant.
Step B : Benzyl (4-{[({2-amino-indan-2-yl}-carbonyl)-amino]-methyl}-phenyl)-(imino)-methyl-carbamate dihydrochloride For 30 minutes, a current of HC1 gas is passed, with stirring, at 0°C, into a solution of the compound described in the Step above (10 mmol) in ethyl acetate. After stirring overnight at ambient temperature, the precipitate formed is filtered off, rinsed with ethyl acetate and then dried in vacuo using a desiccator.
Step C: Benzyl {4-[({[2-({(2R)-2-[(tert-butyloxycarbonyl)-amino]-2-cyclohexyl-ethanoyl}-amino)-indan-2-yl]-carbonyl}-amino)-methyl]-phenyl}-(imino)-methylcarbamate To a solution of the compound described in the Step above (10 mmol) and (R)-N-(tert-butyloxycarbonyl)-cyclohexylglycine (10 mmol) in dimethylformamide there are added 0-(l//-benzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (11 mmol), 1-hydroxybenzotriazole hydrate (11 mmol) and diisopropylethylamine (11 mmol). After stirring overnight at ambient temperature, the solvent is evaporated off. The residue obtained is taken up in ethyl acetate. The organic phase is washed, dried and then evaporated. The expected product is obtained after purification of the residue by chromatography on silica gel, using a mixture of dichloromethane/ethyl acetate (1/1) as eluant.
Step D : Benzyl {4-[({[2-({(2R)-2-amino-2-cyclohexylethanoyl}-amino)-indan-2-yl]-carbonyl}-amino)-methyl]-phenyl}-(imino)-me thylcarbamate dihydrochloride For 30 minutes, a current of HC1 gas is passed, with stirring, at 0°C, into a solution of the compound described in the Step above (10 mmol) in ethyl acetate. After stirring overnight at ambient temperature, the precipitate formed is filtered off, rinsed with ethyl acetate and then dried in vacuo using a desiccator.
Step E: Benzyl {[(lR)-2-({2-[({4-[{(benzyloxycarbonyl)-amino}-(imino)-methyl]-benzyl} -amino)-carbonyl] -indan-2-yl}-amino)-l-cyclohexyl-2-oxoethyl/ -amino}-acetate To a solution of the compound described in the Step above (10 mmol) in acetonitrile there are added potassium carbonate (30 mmol) and then benzyl 2-bromoacetate (11 mmol). After stirring overnight, the solution is filtered and evaporated; the residue is taken up in ethyl acetate, and the organic phase is washed, dried and evaporated.
Step F: {[(lR)-2-({2-[({4-Amidinobenzyl}-amino)-carbonyl]-indan-2-yl}-amino)-l-cyclohexyl-2-oxoethyl]-amino}acetic acid hydrochloride A solution of the compound described in the Step above (10 mmol) in ethanol is placed under hydrogen overnight in the presence of 10 % Pd/C (0.5 g). After filtering off the catalyst, the solvent is evaporated off to yield, after conversion into a salt using hydrochloric acid, the expected product.
Elemental microanalysis: %oC %>H %oN %Cl Calculated: 62.04 6.69 12.92 6.54 Found: 61.61 6.35 12.74 7.86 EXAMPLE 2: {[(lR)-2-({l-[({4-AmidmobeiizyI}-amiiiG)-carboiiyI]-cycIahexyl}-amino)-l-cyclohexyl-2-oxoethyl]-amino}acetic acid hydrochloride The expected product is obtained according to the procedure described in Example 1, replacing the 2-[(tert-butyloxycarbonyl)-amino]-2-indancarboxylic acid by l-[(tert-butyloxycarbonyl)-amino]-cyclohexanecarboxylic acid.
El_ementaJ micrpanaly.s_is : %oC %H %N %Cl Calculated: 59.10 7.54 13.78 6.98 Found: 59.20 7.30 13.52 8.09 EXAMPLE 3; [((lR)-2-{[2-({4-Ainidinobenzyl}-amino)-l,l-dimethyl-2-oxoethyl]-amino}-l-cycIohexyI-2-oxoethyl)-amino]acetic acid hydrochloride The expected product is obtained according to the procedure described in Example 1, replacing the 2-[(tert-butyloxycarbonyl)-amino]-2-indancarboxylic acid by N-(tert-butyloxy-carbonyl)-2-methylalanine.
EXAMPLE 4: N-<4-Amidinobenzyl)-2-({(2R)-2-[(beiizylsulphonyl)-aiiiino]-2- cyclohexyIethanoyl}-amino)-2-methylpropionamide hydrochloride The expected product is obtained according to the procedure described in Example 1, starting from N-(tert-butyloxycarbonyl)-2-methylalanine, the compound described in Preparation A, (R)-N-(tert-butyloxycarbonyl)-cyclohexylglycine and phenylmethane-sulphonyl chloride.
Elemental microanalysis : %oC %>H %oN %Cl %oS Calculated: 57.48 6.79 12.41 6.28 .68 Found: 57.75 6.97 12.35 .94 .59 EXAMPLE 5: N-(4-Amidinobenzyl)-l-({(2R)-2-[(benzylsulphonyl)-amino]-2-cyclo-^ hexylethanoyl}-amino)-cyclopentanecarboxamide hydrochloride The expected product is obtained according to the procedure described in Example 1, starting from l-[(tert-butyloxycarbonyl)-amino]-cyclopentanecarboxylic acid, the compound described in Preparation A, (R)-N-(tert-butyloxycarbonyl)-cyclohexylglycine and phenylmethanesulphonyl chloride.
EXAMPLE 6: N-(4-AmidinobenzyI)-2-({(2R)-2-[([l,r-biphenyIJ-4-yI-suIphonyI)-amino]-2-cycIohexylethanoyl}-amino)-2-methylpropionamide hydrochloride The expected product is obtained according to the procedure described in Example 1, starting from N-(tert-butyloxycarbonyl)-2-methylalanine, the compound described in Preparation A, (R)-N-(tert-butyloxycarbonyl)-cyclohexylglycine and [l,l'-biphenyl]-4-sulphonyl chloride.
Elemental microaaidysis : %C %>H %N %Cl %S Calculated : 61.38 6.44 11.18 .66 .12 Found: 60.47 6.51 11.00 6.00 4.86 EXAMPLE 7; N-(4-Amidinobenzyl)-2-({(2R)-2-[(phenylsulphonyl)-amino]-2- cyclohexylethanoyl}-amino)-2-methylpropionamide hydrochloride The expected product is obtained according to the procedure described in Example 1, starting from N-(tert-butyloxycarbonyl)-2-methylalanine, the compound described in Preparation A, (R)-N-(tert-butyloxycarbonyl)-cyclohexylglycine and benzenesulphonyl chloride.
El_ementaj micrpanalxsjs : %>C %oH %N %Cl %oS Calculated: 55.30 6.51 12.40 8.79 .68 Found: 54.67 6.58 12.74 8.89 .06 EXAMPLE 8: N-(4-Amidinobenzyl)-2-({(2R)-2-[(2-naphthylsuIphonyI)-amino]-2-cyclohexylethanoyI}-amino)-2-methyIpropionamide hydrochloride The expected product is obtained according to the procedure described in Example 1, starting from N-(tert-butyloxycarbonyl)-2-methylalanine, the compound described in Preparation A, (R)-N-(tert-butyloxycarbonyl)-cyclohexylglycine and 2-naphthalene-sulphonyl chloride.
ElementaJ microanalysis : %oC %>H %N %Cl %oS Calculated : 60.04 6.38 11.67 .91 .34 Found: 60.03 6.47 11.37 .79 .25 EXAMPLE 9: N-(4-Amidinobenzyl)-2-({(2R)-2-[[4-(4-pyridyloxy)-phenyl-suIphonyl]-amino]-2-cycIohexylethanoyI}-amino)-2-methyl-propionamide dihydrochloride The expected product is obtained according to the procedure described in Example 1, starting from N-(tert-butyloxycarbonyl)-2-methylalanine, the compound described in Preparation A, (R)-N-(tert-butyloxycarbonyl)-cyclohexylglycine and 4-(4-pyridyloxy)-benzenesulphonyl chloride.
El_ementaj microanalysis : %oC %>H %>N %Cl %S Calculated: 54.78 .93 12.36 .43 4.72 Found 55.16 6.02 12.24 .37 4.41 EXAMPLE 10: N-(4-Amidinobenzyl)-2-({(2R)-2-[(benzylsuIphonyI)-amino]-2-phenylethanoyl}-amino)-2-methylpropionamide hydrochloride The expected product is obtained according to the procedure described in Example 1, starting from N-(tert-butyloxycarbonyl)-2-methyIalanine, the compound described in Preparation A, (R)-N-(tert-butyloxycarbonyl)-phenylglycine and phenylmethanesulphonyl chloride. llementaj microanalysis : %>C %oH %N %Cl %S Calculated: 58.11 .78 12.55 6.35 .75 Found 58.05 .84 12.45 6.34 .76 EXAMPLE 11: N-(4-Amidinobenzvl)-2-(((2R)-2-f[(4-pvridvI)-methvl-suIphonvn-amino]-2-cycIohexylethanoyl}-amino)-2-methyIpropionamide dihydrochloride The expected product is obtained according to the procedure described in Example 1, starting from N-(tert-butyloxycarbonyl)-2-methylalanine, the compound described in Preparation A, (R)-N-(tert-butyloxycarbonyl)-cyclohexylglycine and (4-pyridyl)-methanesulphonyl chloride.
ELemental microanalysis: %C %H %oN %Cl %S Calculated: 51.91 6.37 13.97 11.79 .33 Found 52.53 6.22 14.21 .93 .07 EXAMPLE 12: {[(lR)-2-({l-[({4-Amidinobenzyl}-amino)-carbonyl]-cyclopentyI}-ammo)-l-(dicyclohexylmethyl)-2-oxoethyI]-aiiiino}acetic acid hydrochloride The expected product is obtained according to the procedure described in Example 1, starting from l-[(tert-butyloxycarbonyl)-amino]-cyclopentanecarboxylic acid, the compound described in Preparation A, (R)-N-(tert-butyloxycarbonyl)-dicyclohexylalanine and benzyl 2-bromoacetate.
EtementaJ microanalysis : %C %,H %>N %Cl Calculated: 61.57 8.07 11.58 8.21 Found 61.58 8.00 11.25 7.75 EXAMPLE 13: N-(4-AmidinobenzvB-2-({(2R)-2-[(cvcIohexvImethylsulr>honvD-amino]-2-cyclohexylethanoyl}-amino)-2-methyIpropionamide hydrochloride The expected product is obtained according to the procedure described in Example 1, starting from N-(tert-butyloxycarbonyl)-2-methylalanine, the compound described in Preparation A, (R)-N-(tert-butyloxycarbonyl)-cyclohexylglycine and cyclohexylmethane-sulphonyl chloride.
Eiementaj microanalysis : %oC %H %oN %oCl %S Calculated: 56.88 7.78 12.28 6.22 .62 Found: 56.95 7.74 12.16 6.49 .35 EXAMPLE 14: N-(4-Amidinobenzyl)-2-({(2R)-2-[(4-morpholinylsulphonyl)-amino]-2-cyclohexylethanoyl}-amino)-2-methylpropionamide hydrochloride The expected product is obtained according to the procedure described in Example 1, starting from N-(tert-butyloxycarbonyl)-2-methylalanine, the compound described in Preparation A, (R)-N-(tert-butyloxycarbonyI)-cyclohexylglycine and 4-morpholine-sulphonyl chloride.
ElementaJjnicrpanalysis : %oC %>H %oN %Cl %oS Calculated: 51.56 7.03 .03 6.34 .73 Found: 51.67 6.69 .10 7.12 .37 EXAMPLE 15: N-(4-Amidinobenzyl)-2-({(2R)-2-[[3-(4-morpholinyl)-propyl- suIphonyl]-amino]-2-cyclohexylethanoyl}-amino)-2-methylpropion-amide dihydrochloride The expected product is obtained according to the procedure described in Example 1, starting from N-(tert-butyloxycarbonyl)-2-methylalanine, the compound described in Preparation A, (R)-N-(tert-butyloxycarbonyl)-cyclohexylglycine and 3-(4-morpholinyl)-propanesulphonyl chloride.
ELementaj microanalysis: %C %H %oN %Cl %oS Calculated : 50.85 7.29 13.18 11.12 4.70 Found: 50.92 7.07 13.41 11.56 4.70 EXAMPLE 16: N-(4-Amidmobenzyl)-2-({(2R)-2-[(benzyIsulphonyl)-amino]-2-cyclohexylethanoyI}-amino)-2-indancarboxamide hydrochloride The expected product is obtained according to the procedure described in Example 1, starting from 2-[(tert-butyloxycarbonyl)-amino]-2-indancarboxylic acid, the compound described in Preparation A, (R)-N-(tert-butyloxycarbonyl)-cyclohexylglycine and phenylmethanesulphonyl chloride.
ELementaj microanalysis : %oC %H %oN %oCl %S Calculated: 62.10 6.32 .97 .55 .02 Found: 62.61 6.36 .88 .61 4.99 EXAMPLE 17: N-(4-Amidinobenzyl)-l-({(2R)-2-[(benzylsulphonyl)-amino]-2- cyclohexylethanoyl}-amino)-cyclohexanecarboxamide hydrochloride The expected product is obtained according to the procedure described in Example 1, starting from l-[(tert-butyIoxycarbonyl)-amino]-cyclohexanecarboxylic acid, the compovind described in Preparation A, (R)-N-(tert-butyloxycarbonyl)-cyclohexylglycine and phenylmethanesulphonyl chloride.
El_ementaJjnicrpanalysjs: %oC %>H %oN %oCl %oS Calculated : 59.64 7.01 11.59 .87 .31 Found: 59.38 7.11 11.40 6.16 .07 EXAMPLE 18: {[(lR)-2-({l-[({4-Amidinobenzyl}-amino)-carbonyl]-cycIopentyI}-amino)-l-cycIohexyl-2-oxoethyl]-amino}-acetic acid hydrochloride The expected product is obtained according to the procedure described in Example 1, starting from l-[(tert-butyloxycarbonyl)-amino]-cyclopentanecarboxylic acid, the compound described in Preparation A, (R)-N-(tert-butyloxycarbonyl)-cyclohexylglycine and benzyl 2-bromoacetate.
Elemental jnicroanalxsjs : %oC %>H %oN %>Cl Calculated: 57.08 7.26 13.87 9.13 Found: 57.03 7.17 13.40 9.31 EXAMPLE 19: N-(4-Amidinobenzyl)-2-({(2R)-2-|(henzyIsulphonyl)-amino]-2-benzylethanoyl}-amino)-2-methylpropionamide hydrochloride The expected product is obtained according to the procedure described in Example 1, starting from N-(tert-butyloxycarbonyl)-2-methylalanine, the compound described in Preparation A, (R)-N-(tert-butyloxycarbonyl)-phenylalanine and phenylmethanesulphonyl chloride.
ELementd micrpamalysjs: %>C %H %N %Cl %S Calculated: 58.78 .99 12.24 6.20 .60 Found: 59.28 6.10 11.99 6.21 .57 EXAMPLE 20 : Ethyl {[(lR)-2-({2-[({4-[amino-(hydroxyimino)-raethyl]-benzyl}-amino)-carbonyl]-indan-2-yl}-amino)-l-cyciohexyl-2-oxoethyl]-amino}-acetate The expected product is obtained according to the procedure described in Example 1, starting from 2-[(tert-butyloxycarbonyl)-amino]-2-indancarboxylic acid, the compound described in Preparation B, (R)-N-(tert-butyloxycarbonyl)-cyclohexylglycine and ethyl 2-bromoacetate.
Elemental microanalysis: %oC %H %N Calculated: 65.55 7.15 12.74 Found: 65.47 6.91 12.59 EXAMPLE 21; 2-{[(2R)-2-Amino-2-eyclohexylethanoyl]-amino}-N-[(6-amino-2-methyl-3-pyridyl)-methyI]-2-indancarboxamide dihydrochloride Step A : 2-Amino-N-[(6-amino-2-methyl-3-pyridyl)-methyl]-2-indancarboxamide dihydrochloride The expected product is obtained according to the procedure described in Steps A and B of Example 1, starting from 2-[(tert-butyloxycarbonyl)-amino]-2-indancarboxylic acid and the compound described in Preparation C.
StepB : 2-{[(2R)-2-Amino-2-cyclohexylethanoyl]-amino}-N-[(6-amino-2-methyl-3-pyridyl)-methylJ-2-indancarboxamide dihydrochloride The expected product is obtained according to the procedure described in Steps C and D of Example 1, starting from the compound obtained in the Step above and (R)-N-(tert-butyloxycarbonyl)-cyclohexylglycine.
ELementaJ microanalysis : %C %H %N %Cl Calculated: 59.05 6.94 13.77 13.94 Found: 59.35 6.55 13.60 14.27 EXAMPLE 22: {[(lR)-2-({2-[({[6-Amino-2-methyl-3-pyridyI]-methyl}-amino)- carbonylJ-indan-2-yl}-amino)-l-cyclohexyl-2-oxoethyl]-amino}acetic acid dihydrochloride The expected product is obtained according to the procedure described in Example 1, starting from 2-[(tert-butyloxycarbonyl)-amino]-2-indancarboxylic acid, the compound described in Preparation C, (R)-N-(tert-butyloxycarbonyl)-cyclohexylglycine and benzyl 2-bromoacetate.
Elemental jnicrpanalys_is: %C %H %oN %>Cl Calculated: 57.24 6.58 12.36 12.52 Found: 57.53 6.58 12.31 12.08 EXAMPLE 23; N-{(6-Amino-2-methyl-3-pyridyl)-itiethyl}-2-({(2R)-2-[(benzyl-sulphonyl)-amino]-2-cyclohexylethanoyI}-amino-2-indan-carboxamide hydrochloride The expected product is obtained according to the procedure described in Example 1, starting from 2-[(tert-butyloxycarbonyl)-amino]-2-indancarboxylic acid, the compound described in Preparation C, (R)-N-(tert-butyloxycarbonyl)-cyclohexylglycine and phenylmethanesulphonyl chloride.
Elemental .microanalysis ; %C %H %oN %>Cl %S Calculated: 61.38 6.44 11.18 .66 .12 Found: 61.30 6.54 .94 .74 4.83 EXAMPLE 24: [((lR)-2-{[2-({4-Amidinobenzyl}-amino)-l,l-dimethyl-2-oxoethylJ-amino}-l-phenyI-2-oxoethyI)-amino] acetic acid hydrochloride The expected product is obtained according to the procedure described in Example 1, starting from N-(tert-butyloxycarbonyl)-2-methylalanine, the compound described in Preparation A, (R)-N-(tert-butyloxycarbonyl)-phenylglycine and benzyl 2-bromoacetate.
EXAMPLE 25: [((lR)-2-{[2-({[(3-Amino4/MndazoI-6-yl)-methyl]-aimno}-carbonyl)-indan-2-yI]-amino}-l-cyclohexyl-2-oxoethyl)-amino]acetic acid hydrochloride The expected product is obtained according to the procedure described in Example 1, starting from 2-[(tert-butyloxycarbonyl)-amino]-2-indancarboxylic acid, 6-(aminomethyl)-1 //-indazol-3 -amine (the preparation of which is described in Patent Application WO 00/26211), (R)-N-(tert-butyloxycarbonyl)-cyclohexylglycine and benzyl 2-bromoacetate.
EXAMPLE 26: [((lR)-2-{[2-({[(3-Amino-l,2-benzisoxazoI-6-yI)-methyI]-amino}- carbonyl)-indan-2-yl]-ammo}-l-cyclohexyl-2-oxoethyI)-aminolacetie acid trifluoroacetate Step A : [((lR)-2-{[2-({[(3-Amino-l, 2-benzisoxazol-6-yl)-methyl]-amino}- carbonyl)-indan-2-yl]-amino}-l-cyclohexyl-2-oxoethyl)-amino]acetic acid The expected product is obtained according to the procedure described in Steps A to C of Example 1, starting from 2-[(tert-butyloxycarbonyl)-amino]-2-indancarboxylic acid, 6-(aminomethyl)-l,2-benzisoxazol-3-amine (the preparation of which is described in Patent Application WO 00/26210), (R)-N-(tert-butyloxycarbonyl)-cyclohexylglycine and benzyl 2-bromoacetate.
Step B: [((lR)-2-{[2-({[(3-Amino-l,2-benzisoxazol-6-yl)-methyl]-amino}~ carbonyl)-indan-2-yl]-amino}-l-cyclohexyl-2-oxoethyl)-amino]acetic acid trifluoroacetate The expected product is obtained according to the procedure described in Step D of Example 1, replacing the HC1 gas by trifluoroacetic acid.
Elemental microanalysis: %oC %0H %N %oCl Calculated: 59.81 6.42 13.95 7.06 Found 59.75 6.35 13.60 6.76 EXAMPLE 27: {[(lR)-2-({2-[({4-Amidinophenyl}-amino)-carbonyl]-indan-2-yl}-amino)-l-cyclohexyl-2-oxoethyl]-amino}acetic acid hydrochloride The expected product is obtained according to the procedure described in Example 1, replacing the compound of Preparation A by benzyl (4-aminophenyl)-(imino)-methyl-carbamate.
EXAMPLE 28: {[(lR)-2-({2-[({4-AmidinobenzyI}-amino)-carbonyI]-indan-2-yI}-amino)-l-phenyI-2-oxoethyl]-amino}acetic acid dihydrochloride The expected product is obtained according to the procedure described in Example 1, replacing the (R)-N-(tert-butyloxycarbonyl)-cyclohexylglycine by (R)-N-(tert-butyloxy-carbonyl)-phenylglycine.
ElementaJjnicjoanalysjs : %C %H %oN %oCl Calculated: 58.74 .46 12.23 12.39 Found 59.06 .49 12.14 12.13 EXAMPLE 29: {[(lR)-2-({2-[({4-Amidinobenzyl}-amino)-carbonylJ-indan-2-yl)-amino)-l-benzyl-2-oxoethylJ-amino}acetic acid dihydrochloride The expected product is obtained according to the procedure described in Example 1, replacing the (R)-N-(tert-butyloxycarbonyl)-cyclohexylglycine by (R)-N-(tert-butyloxy-carbonyl)-phenylalanine.
Elemental microsmalysjs; %oC %>H %oN %oCl Calculated: 59.39 .67 11.94 12.09 Found 59.70 .65 11.84 11.68 EXAMPLE 30: {[(lR)-2-({2-[({4-Amidinobenzyl}-amino)-carbonyl]-indan-2-yl)-amino)-l-cyclohexylmethyl-2-oxoethyI]-araino}acetic acid dihydrochloride The expected product is obtained according to the procedure described in Example 1, replacing the (R)-N-(tert-butyloxycarbonyl)-cyclohexylglycine by (R)-N-(tert-butyloxy-carbonyl)-cyclohexylalanine.
ElementaJ microanalysis : %C %>H %N %Cl Calculated: 58.78 6.63 11.82 11.97 Found 59.55 6.55 11.92 11.92 EXAMPLE 31: N-[(6-Amino-2-methyl-3-pyridyI)-methyl]-2-[(2-phenethyl)-amino]-2- indancarboxamide dihydrochloride To 10 mmol of the compound described in Step A of Example 21 dissolved in 1,2-dichloroethane there are added 10 mmol of phenylacetaldehyde and then 14 mmol of sodium triacetoxyborohydride. After stirring for 4 hours, water is added and the reaction 10 mixture is then separated and extracted with dichloromethane. The combined organic phases are dried and then filtered and evaporated. The residue thereby obtained is purified by chromatography on silica (eluant: dichloromethane/methanol 95/5) to yield, after conversion into a salt using hydrochloric acid, the expected product.
ELementaJ microanalysis: %C %H %>N %Cl Calculated: 63.42 6.39 11.83 14.98 Found 63.92 6.33 11.89 .36 EXAMPLE 32 : {|(lS)-2-({2-[({4-AmidinobenzyI}-amino)-carbonyl]-indan-2-yl}- amino)-l-cyclohexyl-2-oxoethyl]-amino}acetic acid dihydrochloride The expected product is obtained according to the procedure described in Steps C to F of Example 1, starting from the compound described in Step B of Example 1 and (S)-N-(tert-butyloxycarbonyl)-cyclohexylglycine.
ELementaj microanalysis : %oC %oH %N %Cl Calculated: 58.13 6.45 12.11 12.26 Found: 58.46 6.59 12.02 11.99 EXAMPLE 33 : N-[(6-Amino-2-methyI-3-pyridyl)-methyI]-2-[(2,2-diphenylethyl)-aminoJ-2-indancarboxamide hydrochloride The expected product is obtained according to the procedure described in Example 31, replacing the phenylacetaldehyde by diphenylacetaldehyde.
Eljementajjnicjpanaly.s_is : %oC %>H %>N %Cl Calculated: 61.15 6.24 .20 12.90 Found: 68.15 6.18 .19 12.96 EXAMPLE 34: N-[(6-Amino-2-methyl-3-pyridyl)-methyl]-2-[(3-phenyIpropyl)-amino]-2-indancarboxamide hydrochloride The expected product is obtained according to the procedure described in Example 31, replacing the phenylacetaldehyde by 3-phenylpropanal.
El_emental jnicroanalysis : %C %oH %>N %Cl Calculated: 64.06 6.62 11.49 14.55 Found: 64.74 6.51 11.59 14.68 EXAMPLE 35; N-(4-AmidinobenzyI)-2-[(2,2-diphenylethyl)-amino]-2-indan-carboxamide hydrochloride Step A : Benzyl (4-{[({2-[(2,2-diphenylethyl)-amino]-indan-2-yl}-carbonyl)-amino]-methyl}-phenyl)-(imino)-methylcarbamate hydrochloride The expected product is obtained according to the procedure described in Example 31, starting from the compound obtained in Step B of Example 1 and diphenylacetaldehyde.
StevB : N-(4-Amidinobenzyl)-2-[(2,2-diphenylethyl)-aminoJ-2-indan- carboxamide hydrochloride The expected product is obtained according to the procedure described in Step F of Example 1, starting from the compound obtained in the Step above.
ElementaJ microanalysis : %oC %>H %oN %Cl Calculated: 73.20 6.33 .67 6.75 Found: 72.55 .96 .15 7.42 EXAMPLE 36 : Ethyl ({(lR)-l-cyclohexyl-2-[(2-{[(4-{imino-[(methoxycarbonyl)-amino]-methyl}-benzyl)-amlnoJ-carbonyl}-indan-2-yl)-amino]-2-oxoethyl}-amino)-acetate: The expected product is obtained according to the procedure described in Steps A to E of Example 1, replacing, in Step A, Preparation A by Preparation D and, in Step E, the benzyl 2-bromoacetate by ethyl 2-bromoacetate.
ElementaJ microanalysis ; %oC %>H %oN Calculated: 64.96 6.98 11.84 Found: 64.29 6.91 11.45 EXAMPLE 37: Ethyl ({(lR)-l-cycIohexyl-2-[(2-{[(4-{imino-[({hexyIoxy}-carbonyl)-amino]-methyl}-benzyl)-ainino]-carbonyl}-indan-2-yl)-ammo]-2-oxoethyl}-amino)-acetate: The expected product is obtained according to the procedure described in Steps A to E of Example 1, replacing, in Step A, Preparation A by Preparation E and, in Step E, the benzyl 2-bromoacetate by ethyl 2-bromoacetate.
Elemental microanalysis : %C %H %N Calculated: 67.15 7.77 .58 Found: 67.21 7.85 .57 EXAMPLE 38: N-(4-Amidinobenzyl)-2-({(2R)-2-[(2-ammo-2-oxoethyI)-amiiiol-2-cyclohexylethanoyl}-amino)-2-mdancarboxaiiiide hydrochloride The expected product is obtained according to the procedure of Example 1, replacing the benzyl 2-bromoacetate in Step E by 2-bromoacetamide.
ElementaJ Microanalysis: %oC %>H %oN %oCl Calculated: 62.15 6.89 .53 6.55 Found: 62.77 6.70 .33 6.75 EXAMPLE 39 A : {[(lR)-2-({2-[({4-Amidinobenzyl}-amino)-carbonyl]-indan-2-yl}-amino)-l-isopropyl-2-oxoethyI]-amino}aeetic acid hydrochloride The expected product is obtained according to the procedure of Example 1, replacing the (i?)-N-(tert-butyloxycarbonyl)-cyclohexylglycine in Step C by (i?)-N-(tert-butyloxy-carbonyl)-valine.
ElementaJ microanalysis : %C %>H %N %Cl Calculated: 59.81 6.42 13.95 7.06 Found: 59.75 6.35 13.60 6.76 EXAMPLE 3!? B : {[(lR)-2-({2-[({4-Amidinobenzyl}-amino)-carbonyl]-indan-2-yI}-amino)-l-isopropyl»2-oxoethyI]-amino}acetic acid dihydrochloride ElementaJ microanalysis : %C %H %oN %Cl Calculated: 55.76 6.18 13.01 13.17 Found: 55.62 6.27 12.75 13.45 EXAMPLE 40: N-(4-Amidinobenzyl)-2-[((2R)-2-cyclohexyl-2-{[(cycIohexyImethyl)-sulphonyI]-amino}-ethanoyI)-amino]-2-indancarboxamide hydrochloride The expected product is obtained according to the procedure described in Example 1, starting from 2-[(tert-butyloxycarbonyl)-amino]-2-indancarboxylic acid, the compound described in Preparation A, (R)-N-(tert-butyloxycarbonyl)-cyclohexylglycine and cyclohexylmethanesulphonyl chloride.
El_ementaJ microanalysis : %C %H %>N %Cl %S Calculated: 61.52 7.20 .87 .50 4.98 Found: 61.22 7.22 .67 .49 4.91 EXAMPLE 41: N-(4-AmidinobenzyI)-2-[((2R)-2-cyclohexyl-2-{[(cyclohexylmethyl)- sulphonyl]-amino}-ethanoyl)-amino]-2,3-dihydro-l//-eycIopenta[b]- naphthalene-2-carboxamide hydrochloride The expected product is obtained according to the procedure described in Example 1, starting from 2- [(tert-butyloxycarbonyl)-amino] -2,3 -dihydro-1 //-cyclopenta[b] -naphthalene-2-carboxylic acid, the compound described in Preparation A, (R)-N-(tert-butyloxycarbonyl)-cyclohexylglycine and cyclohexylmethanesulphonyl chloride.
EXAMPLE 42 : N-(4-Amidinobenzyl)-2-[((2R)-2-cycIohexyI-2-{[(cyclohexylmethyI)-sulphonyl]-amino}-ethanoyl)-amino]-2,3-dihydro-l//-cyelopenta[a]-naphthalene-2-carboxamide hydrochloride The expected product is obtained according to the procedure described in Example 1, starting from 2-[(tert-butyloxycarbonyl)-amino]-2,3-dihydro-1 //-cyclopenta[a]-naphthalene-2-carboxylic acid, the compound described in Preparation A, (R)-N-(tert-butyloxycarbonyl)-cyclohexylglycine and cyclohexylmethanesulphonyl chloride.
EXAMPLE 43: N-(4-Amidinobenzyl)-2-[((2R)-2-{[(eyclohexyImethyI)-sulphonyl]-amino}-3-methylbutanoyl)-amino]-2,3-dihydro-l//-cyclopenta[a]-naphthalene-2-carboxamide hydrochloride The expected product is obtained according to the procedure described in Example 1, starting from 2-[(tert-butyloxycarbonyl)-amino]-2,3-dihydro-1 i/-cyclopenta[a]-naphthalene-2-carboxylic acid, the compound described in Preparation A, (R)-N-(tert-butyloxycarbonyl)-valine and cyclohexylmethanesulphonyl chloride.
Elemental microanalysis : %C %>H %>N %Cl %S Calculated: 62.42 6.78 .70 4.90 .42 Found: 62.95 7.02 .65 4.71 .39 EXAMPLE 44: N-(4-Amidinobenzyl)-2-[((2R)-2-{[(cyclohexylmethyl)-sulphonyl]- amino}-3-methylbutanoyl)-amino]-2,3-dihydro-l/2T-cyclopenta[b]- naphthalene-2-carboxamide hydrochloride The expected product is obtained according to the procedure described in Example 1, starting from 2-[(tert-butyloxycarbonyl)-amino] -2,3 -dihydro-1 //-cyclopenta[b] -naphthalene-2-carboxylic acid, the compound described in Preparation A, (R)-N-(tert-butyloxycarbonyl)-valine and cyclohexylmethanesulphonyl chloride.
EXAMPLE 45: {[(lR)-2-({2-[({4-AmidinobenzyI}-amino)-carbonyI]-2,3-dihydro-l//-cyclopenta[b]naphth-2-yl}-amino)-l-cyclohexyI-2-oxoethyl]-amino}-acetic acid hydrochloride The expected product is obtained according to the procedure described in Example 1, replacing the 2-[(tert-butyloxycarbonyl)-amino]-2-indancarboxylic acid in Step A by 2-[(tert-butyloxycarbonyl)-amino]-2,3-dihydro-li/-cyclopenta[b]naphthalene-2-carboxylic acid.
EXAMPLE 46: {[(lR)-2-({2-[({4-Amidinobenzyl}-amino)-carbonyl]-2,3-dihydro-l//-cyclopenta[a]naphth-2-yl}-amino)-l-cyclohexyl-2-oxoethyl]-amino}-acetic acid hydrochloride The expected product is obtained according to the procedure described in Example 1, replacing the 2-[(tert-butyloxycarbonyl)-amino]-2-indancarboxylic acid in Step A by 2-[(tert-butyloxycarbonyl)-amino]-2,3-dihydro-l//-cyclopenta[a]naphthalene-2-carboxylic acid.
EXAMPLE 47: ({(lR)-l-l({2-[({4-Amidinobenzyl}-amino)-carbonyI]«2,3-dihydro-l//-cyclopenta[a]naphth-2-yl}-amino)-carbonyl]-2-methylpropyl}-amino)acetic acid hydrochloride The expected product is obtained according to the procedure described in Example 1, replacing, in Step A, the 2-[(tert-butyloxycarbonyl)-amino]-2-indancarboxylic acid by 2-[(tert-butyloxycarbonyl)-amino]-2,3-dihydro-l//-cyclopenta[a]naphthalene-2-carboxylic acid and, in Step C, the (R)-N-(tert-butyloxycarbonyl)-cyclohexylglycine by (7?)-N-(tert-butyloxycarbonyl)-valine.
El_ementaJjiiicrpanaly.s_is : %C %H %oN %Cl Calculated: 63.09 6.21 12.69 6.42 Found: 63.46 6.08 12.60 6.57 EXAMPLE 48: ({(lR)-l-[({2-[({4-Amidinobenzyl}-amino)-carbonyl]-2,3-dihydro-li/-cydopenta[b]naphth-2-yI}-amino)-carbonyl]-2-methylpropyl}-amino)-acetic acid hydrochloride The expected product is obtained according to the procedure described in Example 1, replacing, in Step A, the 2-[(tert-butyloxycarbonyl)-amino]-2-indancarboxylic acid by 2- [(tert-butyloxycarbonyl)-amino] -2,3 -dihydro-1 //-cyclopenta[b]naphthalene-2-carboxylic acid and, in Step C, the (R)-N-(tert-butyloxycarbonyl)-cyclohexylglycine by (jR)-N-(tert-butyloxycarbonyl)-valine.
El_ementaj micrpanalysis: %C %H %>N %Cl Calculated: 63.09 6.21 12.69 6.42 Found: 63.17 .91 12.39 6.49 EXAMPLE 49: N-(4-Amidinobenzyl)-2-[((2R)-2-{[(cyclohexylmethyI)-sulphonyl]-amino}-3-methylbutanoyl)-amino]-2-indancarboxamide hydrochloride The expected product is obtained according to the procedure described in Example 1, starting from 2-[(tert-butyloxycarbonyl)-amino]-2-indancarboxylic acid, the compound described in Preparation A, (R)-N-(tert-butyloxycarbonyl)-valine and cyclohexylmethanesulphonyl chloride.
ELejnentaJ microanalysis : %>C %H %N %oS %Cl Calculated : 59.64 7.01 11.59 .31 .87 Found: 59.75 7.07 11.43 .22 .92 EXAMPLE 50: N-(4-Amidinobenzyl)-2-[((2R)-2-{[(cyclohexylmethyl)-sulphonyl]-amino}-3-methylbutanoyl)-amino]-2,3-dihydro-l//-phenalene-2-carboxamide hydrochloride The expected product is obtained according to the procedure described in Example 1, starting from 2- [(tert-butyloxycarbonyl)-amino] -2,3 -dihydro-1 /f-phenalene-2-carboxylic acid, the compound described in Preparation A, (R)-N-(tert-butyloxycarbonyl)-valine and cyclohexylmethanesulphonyl chloride.
El_ement_a_l microanalysis ; %oC %H %N %oS %Cl Calculated: 62.42 6.78 .70 4.90 .42 Found: 62.79 7.58 .63 4.49 .31 EXAMPLE 51: ({(lR)-l-[({2-[({4-Amidinobenzyl}-amino)-carbonyl]-2,3-dihydro-l//-phenaIen-2-yl}-amino)-carbonyl]-2-methylpropyl}-amino)-acetic acid dihydrochloride The expected product is obtained according to the procedure described in Example 1, replacing, in Step A, the 2-[(tert-butyloxycarbonyl)-amino]-2-indancarboxylic acid by 2-[(tert-butyloxycarbonyl)-amino]-2,3-dihydro-l//-phenalene-2-carboxylic acid and, in Step C, the (R)-N-(tert-butyloxycarbonyl)-cyclohexylglycine by (i?)-N-(tert-butyloxy-carbonyl)-valine.
El_ementaj microanalysis : %C %>H %N %Cl Calculated: 59.18 .99 11.90 12.05 Found: 59.56 .59 11.85 11.25 EXAMPLE 52: N-(4-Amidinobenzyl)-2-[((2R)-2-{[isobutylsulphonyI]-amino}-3-raethylbutanoyl)-amino]-2-indancarboxamide hydrochloride The expected product is obtained according to the procedure described in Example 1, starting from 2-[(tert-butyloxycarbonyl)-amino]-2-indancarboxylic acid, the compound described in Preparation A, (R)-N-(tert-butyloxycarbonyl)-valine and isobutanesulphonyl chloride.
El_ementaJjnicrpanalysjs : %oC %H %oN %S %Cl Calculated: 57.48 6.79 12.41 .68 6.28 Found: 57.77 6.93 12.28 .41 6.38 EXAMPLE 53: ({(lR)-l-[({6-[({4-Amidinobenzyl}-ainino)-carbonyl]-6,7-dihydro-5//-dibenzo [a,c] cyclohepten-6-yl}-amino)-carbonyl] -2-methyIpropyl}-amino)-acetic acid dihydrochloride The expected product is obtained according to the procedure described in Example 1, replacing, in Step A, the 2-[(tert-butyloxycarbonyl)-amino]-2-indancarboxylic acid by 6-[(tert-butyloxycarbonyl)-amino]-6,7-dihydro-5//-dibenzo[a,c]cycloheptene-6-carboxylic acid and, in Step C, the (R)-N-(tert-butyloxycarbonyl)-cyclohexylglycine by (i?)-N-(tert-butyloxycarbonyl)-valine.
ELementaj microamalysjs : %oC %oH %N Ho CI Calculated: 60.59 6.07 11.40 11.54 Found: 61.11 6.11 11.34 11.68 EXAMPLE 54: N-(4-Cyanobenzyl)-2-[((2R)-2-{[(cycIohexylmethyl)-sulphonyl]-amino}-3-methylbutanoyI)-ammo]-2-indaiicarboxamide The expected product is obtained according to the procedure described in Steps A to E of Example 1, replacing, in Step A, the compound of Preparation A by 4-(aminomethyl)benzonitrile and, in Step E, the benzyl 2-bromoacetate by cyclohexylmethanesulphonyl chloride.
Elemental microanalysis : %oC %oH %N HoS Calculated: 65.43 6.95 .17 .82 Found: 65.28 6.93 .17 .73 EXAMPLE 55: N-{4-[(Hydroxyamino)-(imino)-methyl]-benzyI}-2-[((2R)-2-{[(cycIo-hexylmethyl)-sulphonyl]-amino}-3-methylbutanoyl)-amino]-2-indan-carboxamide The expected product is obtained according to the procedure described in Steps A to E of Example 1, replacing, in Step A, the compound of Preparation A by the compound of Preparation F and, in Step E, the benzyl 2-bromoacetate by cyclohexylmethanesulphonyl chloride.
El_ementaJ microanalysis ; HoC %H %N %oS Calculated: 61.73 7.08 12.00 .49 Found: 61.52 7.06 11.99 .16 EXAMPLE 56: {[2-({2-[({4-Amidinobenzyl}-amino)-carbonyI]-indan-2-yl}-amino)-l,l-dlmethyl-2-oxoethyl]-amino}acetic acid dihydrochloride The expected product is obtained according to the procedure described in Example 1, replacing the (R)-N-(tert-butyloxycarbonyl)-cyclohexylglycine in Step C by N-(tert-butyloxycarbonyl)-2-methylalanine.
Elemental microanalysis : HoC %H %N %Cl Calculated: 54.97 .96 13.35 13.52 Found: 54.97 .84 13.13 12.69 EXAMPLE 57: ({l-[({2-[({4-Amidinobenzyl}-amino)-carbonyI]-indan-2-yl}-amino)-carbonyl]-cyclopentyl}-aiiimo)-acetic acid dihydrochloride The expected product is obtained according to the procedure described in Example 1, replacing the (R)-N-(tert-butyloxycarbonyl)-cyclohexylglycine in Step C by l-[(tert-butyloxycarbonyl)-amino] -cyclopentanecarboxylic acid.
ElementaJ microanalysis : %C %>H %>N %Cl Calculated: 56.73 6.04 12.72 12.88 Found: 56.57 .92 12.61 12.23 EXAMPLE 58: ({(lR)-l-[({2-[({4-Amidinobenzyl}-amino)-carbonyl]-indan-2-yI}-amino)-carbonyl]-propyl}-amino)-acetic acid dihydrochloride The expected product is obtained according to the procedure described in Example 1, replacing the (R)-N-(tert-butyloxycarbonyl)-cyclohexylglycine in Step C by (2R)-2-[(tert-butyloxycarbonyl)-amino]-butanoic acid.
ELementaJjnicroanalxsjs: %C %oH %N %Cl Calculated: 54.97 .96 13.35 13.52 Found: 54.68 .85 13.14 12.87 EXAMPLE 59: ({(lR,2R)-l-[({2-[({4-Amidmobenzyl}-amino)-carbonyl]-indan-2-yl}-amino)-carbonyl]-2-methyIbutyl}-amino)-acetic acid dihydrochloride The expected product is obtained according to the procedure described in Example 1, replacing the (R)-N-(tert-butyloxycarbonyl)-cyclohexylglycine in Step C by (2R,3R)-N-(tert-butyloxycarbonyl)-isoleucine.
ELementaJ microanalysis : %oC %H %N %Cl Calculated: 56.52 6.39 12.68 12.83 Found: 57.26 6.43 12.69 12.61 EXAMPLE 60: ({(lR)-l-[({2-[({4-Amidinobenzyl}-amino)-carbonyl]-indan-2-yl}-amino)-carbonyl]-2,2-dimethylpropyl}-amino)-acetic acid dihydrochloride The expected product is obtained according to the procedure described in Example 1, replacing the (R)-N-(tert-butyloxycarbonyl)-cyclohexylglycine in step C by (2R)-2-[(tert-butyloxycarbonyl)-amino] -3,3 -dimethylbutanoic acid.
El_ement_a_l jnicroanalysjs : %oC %oH %>N %Cl Calculated: 56.52 6.39 12.68 12.83 Found: 56.98 6.36 12.61 12.34 EXAMPLE 61: Diastereoisomer 1 of ({(lR)-l-[({6-[({4-amidinobenzyl}-amino)-carbonyl]-6,7-dihydro-5//-cyclopenta[b]pyridin-6-yl}-amino)-carbonyl]-2-methyIpropyI}-amino)-acetic acid trihydrochloride Step A : Diastereoisomer 1 of benzyl ({(lR)-l-[({6-[({4-[{[(benzyloxy)-carbonylJ-amino}-(imino)-methyl]-benzyl}-amino)-carbonyl]-6,7-dihydro-5H-cyclopenta[b]pyridin-6-yl}-amino)-carbonyl]-2-methylpropyl}-amino)-acetate The expected product is obtained according to the procedure described in Steps A to E of Example 1, replacing, in Step A, the 2-[(tert-butyloxycarbonyl)-amino]-2-indancarboxylic acid by 6-[(tert-butyloxycarbonyl)-amino]-6,7-dihydro-5//-cyclopenta[b]pyridine-6-carb-oxylic acid and, in Step C, the (R)-N-(tert-butyloxycarbonyl)-cyclohexylglycine by (R)-N-(tert-butyloxycarbonyl)-valine, and then separating the mixture of diastereoisomers thereby obtained by chromatography on silica.
The expected product is the first of the diastereoisomers separated in that manner.
Step B: Diastereoisomer 1 of ({(lR)-l-[({6-[({4-amidinobenzyl}-amino)-carbonyl]~ 6,7-dihydro-5H-cyclopenta[b]pyridin-6-yl}-amino)-carbonyl]-2-methyl-propyl}-amino)-acetic acid trihydrochloride The expected product is obtained according to the procedure described in StepF of Example 1, starting from the compound obtained in the Step above.
ElementaJ microanalysis : %>C %H %N %Cl Calculated: 50.05 5.78 14.59 18.47 Found: 50.39 5.71 14.54 18.37 EXAMPLE 62 : Diastereoisomer 2 of ({(lR)-l-[({6-[({4-araidinobenzyl}-amino>-carbonyl]-6,7-dihydro-5//-cycIopenta[b]pyridin-6-yl}-amino)-carbonyl]-2-methy!propyl}-amino)-acetic acid trihydrochloride Step A : Diastereoisomer 2 of benzyl ({(lR)-l-[({6-[({4-[{[(benzyloxy)-carbonyl]~ amino}-(imino)-methyl]-benzyl}-amino)-carbonyl]-6,7-dihydro-5H-cyclopenta[b]pyridin-6-yl}-amino)-carbonyl]-2-methylpropyl}-amino)-acetate The expected product is the second of the diastereoisomers separated in Step A of Example 61.
Step B: Diastereoisomer 2 of ({(lR)-l-[({6-[({4-amidinobenzyl}-amino)carbonyl]~ 6,7-dihydro-5H-cyclopenta[b]pyridin-6-yl}-amino)-carbonyl]-2-methyl-propyl}-amino)-acetic acid trihydrochloride The expected product is obtained according to the procedure described in Step F of Example 1, starting from the compound obtained in the Step above.
ELemented microanalysis: %>C HoH %N %Cl Calculated: 50.05 .78 14.59 18.47 Found: 50.14 .56 14.45 19.00 EXAMPLE 63 : Hexyl (4-{[({2-[((2R)-2-{[(cyelohexylmethyl)-sulphoiiyl]-aniiiio}-3-methylbutanoyl)-amino]-indan-2-yl}-carbonyl)-amino]-methyl}-phenyl)-(imino)-methylcarbamate The expected product is obtained according to the procedure described in Steps A to E of Example 1, starting from 2-[(tert-butyloxycarbonyl)-amino]-2-indancarboxylic acid, the compound described in Preparation E, (R)-N-(tert-butyloxycarbonyl)-valine and cyclohexylmethanesulphonyl chloride.
El_ementaJ microanalysis : %C %H %oN %S Calculated: 63.86 7.68 .06 4.61 Found: 64.10 7.93 9.89 4.30 EXAMPLE 64; N-(4-Amidinoben/yl)-6-[((2R)-2-{[(cycIohexylmethyl)-suIphonylJ-ammo}-3-methylbutanoyI)-amino]-6,7-dihydro-5//-cycIopenta[b]-pyridine-6-carboxamide dihydrochloride The expected product is obtained according to the procedure described in Example 1, starting from 6-[(tert-butyloxycarbonyl)-amino]-6,7-dihydro-5i/-cyclopenta[b]pyridine-6-carboxylic acid, the compound described in Preparation A, (R)-N-(tert-butyloxycarbonyl)-valine and cyclohexylmethanesulphonyl chloride.
Elemental microanalysis : %oC HoH %N HoS %Cl Calculated: 54.28 6.60 13.10 .00 11.05 Found: 54.57 6.57 13.05 4.99 .85 EXAMPLE 65: ({(lR)-l-[({6-[({4-Amidinobenzyl}-amino)carbonyl]-6,7-dihydro-5/f-cyclopentalc]pyridin-6-yI}-amino)-carbonyIJ-2-methylpropyI}-amino)-acetic acid trihydrochloride The expected product is obtained according to the procedure described in Example 1, replacing, in Step A, the 2-[(tert-butyloxycarbonyl)-amino]-2-indancarboxylic acid by 6-[(tert-butyloxycarbonyl)-amino]-6,7-dihydro-5H-cyclopenta[c]pyridine-6-carboxylic acid and, in Step C, the (R)-N-(tert-butyloxycarbonyl)-cyclohexylglycine by (R)-N-(tert-butyloxycarbonyl)-valine.
EXAMPLE 66: N-(4-Amidinobenzyl)-2-{[(2R)-2-(isobutylamino)-3-methylbutanoyl]-amino}-2-indancarboxamide dihydrochloride The expected product is obtained according to the procedure described in Example 1, starting from 2-[(tert-butyloxycarbonyl)-amino]-2-indancarboxylic acid, the compound described in Preparation >A, N-(tert-butyloxycarbonyl)-glycine and isobutyl chloride.
Elemental .microanalysis : %>C %H %oN %Cl Calculated: 58.30 6.73 14.16 14.34 Found: 57.97 6.86 14.19 14.92 EXAMPLE 67: N-[(6-Amino-2-methyl-3-pyridyl)-methylJ-2-{[(2R)-2-(isobutyl-amino)-3-methylbutanoyl]-amino}-2-indancarboxamide dihydrochloride The expected product is obtained in the form of the base according to the procedure described in Steps C to E of Example 1, starting from the compound obtained in Step A of Example 21, N-(tert-butyloxycarbonyl)-glycine and isobutyl chloride, and is then converted into a salt using hydrochloric acid.
Elemental .microanalysis: %C %>H %N %Cl Calculated: 57.26 6.89 14.52 14.70 Found: 57.17 7.02 14.49 14.95 EXAMPLE 68: {[2-({2-[({4-Amidinobenzyl}-amino)-earbQiiyl]-indan-2-yl}-amino)-2-oxoethyl]-amino} acetic acid dihydrochloride The expected product is obtained according to the procedure described in Example 1, replacing the (R)-N-(tert-butyloxycarbonyl)-cyclohexylglycine in Step C by N-(tert-butyloxycarbonyl)-glycine.
El_ementaJjnkrpanaly.s_is : HoC HoH %oN %> CI Calculated: 53.23 .48 14.11 14.28 Found: 53.40 .56 14.00 14.32 EXAMPLE 69: {[(lR)-2-({2-[({4-Amidinobenzyl}-amino)-carbonyll-5,6-dimethoxy-indan-2-yI}-amino)-l-isopropyI-2-oxoethyIj-amino}-acetic acidi hydrochloride The expected product is obtained according to the procedure of Example 1, replacing, in Step A, the 2-[(tert-butyloxycarbonyl)-amino]-2-indancarboxylic acid by 2-[(tert-butyloxycarbonyl)-amino]-5,6-dimethoxy-2-indancarboxylic acid and, in Step C, the (R)-N-(tert-butyloxycarbonyl)-cyclohexylglycineby (R)-N-(tert-butyloxycarbonyl)-valine.
ELemental microanalysis : %C HoH HoN Ho CI Calculated: 57.70 6.46 12.46 6.31 Found: 58.06 6.32 12.50 6.78 EXAMPLE 70: ({(lR)-l-[({2-[({4-Amidinobenzyl}-amino)-carbonyl]-indan-2-yl}-amino)-carbonyl]-3-methylbutyl}-amino)-acetic acid hydrochloride The expected product is obtained according to the procedure described in Example 1, replacing the (R)-N-(tert-butyloxycarbonyl)-cyclohexylglycine in Step C by (R)-N-(tert-butyloxycarbonyl)-leucine.
ElementaJ micrpanalxsis : %C HoH %N Ho CI Calculated : 60.52 6.64 13.57 6.87 Found: 60.39 6.53 13.40 7.56 EXAMPLE 71: {[(lR)-2-({2-[({4-AmidinobenzyI}-amino)-carbonyIJ-indan-2-yI}-amino)-l-methyI-2-oxoethyl]-amino}acetic acid dihydrochloride The expected product is obtained according to the procedure described in Example 1, replacing the (R)-N-(tert-butyloxycarbonyl)-cyclohexylglycine in Step C by (R)-N-(tert-butyloxycarbonyl)-alanine.
Elemental microanalysis : HoC HoH HoN Ho CI Calculated : 54.12 .73 13.72 13.89 Found: 54.34 .87 13.53 14.35 EXAMPLE 72; N-(4-Amidinobenzyl)-2-[((2R)-2-{[isobutyIsulphonyl]-amino}-3-methylbutanoyl)-amino]-5,6-dimethoxy-2-indancarboxamide hydrochloride The expected product is obtained according to the procedure described in Example 1, starting from 2-[(tert-butyloxycarbonyl)-amino]-5,6-dimethoxy-2-indancarboxylic acid, the compound described in Preparation A, (R)-N-(tert-butyloxycarbonyl)-valine and isobutanesulphonyl chloride.
.ElementaJ microanalysis: %>C %H HoN %S %> CI Calculated: 55.80 6.78 11.22 .14 .68 Found: 55.58 6.94 11.21 4.90 6.01 EXAMPLE 73; {[(lR)-l-({[(lS)-2-({4-Amidinobenzyl}-amino)-l-benzyl-2-oxoethyl]-a m ino}-ca r bo nyl)-2-me thy lpropyl] amino}-acetic acid dihydrochloride The expected product is obtained according to the procedure of Example 1, replacing, in Step A, the 2-[(tert-butyloxycarbonyl)-amino]-2-indancarboxylic acid by (S)-N-(tert- butyloxycarbonyl)-phenylalanine and, in Step C, the (R)-N-(tert-butyloxycarbonyl)-cyclohexylglycine by (R)-N-(tert-butyioxycarbonyl)-valine.
El_ementaJ jnicrpanalysjs : %oC %>H HoN Ho CI Calculated: ^ - 54.75 6.32 13.30 13.47 Found: 54.90 6.40 13.27 13.08 EXAMPLE 74 : ({(lR)-l-[({(lS)-2-[{4-AmidinobenzyI}-amino)-1-benzhydry 1-2-oxoethyl]-amino}-carbonyl)-2-methylpropyl]amino}-acetic acid dihydrochloride The expected product is obtained according to the procedure of Example 1, replacing, in Step A, the 2-[(tert-butyloxycarbonyl)-amino]-2-indancarboxylic acid by (2S)-2-[(tert-butyloxycarbonyl)-amino]-3,3-diphenylpropanoic acid and, in Step C, the (R)-N-(tert-butyloxycarbonyl)-cyclohexylglycine by (R)-N-(tert-butyloxycarbonyl)-valine.
ElementaJ micjoanalysjs : %C %H %N Ho CI Calculated: 59.80 6.19 11.62 11.77 Found: 60.35 6.15 11.88 11.62 EXAMPLE 75: ({(lR)-l-[({(lS)-2-[{4-Amidinobenzyl}-amino)-l-(2,3-dihydro-lH-inden-2-yl)-2-oxoethyl]-amino}-carbonyl)-2-methylpropyl]-amino}-acetic acid dihydrochloride The expected product is obtained according to the procedure of Example 1, replacing, in Step A, the 2-[(tert-butyloxycarbonyl)-amino]-2-indancarboxylic acid by (2S)-2-[(tert-butyloxycarbonyl)-amino]-(2,3-dihydro-l//-inden-2-yl)ethanoic acid and, in Step C, the (R)-N-(tert-butyloxycarbonyl)-cyclohexylglycine by (R)-N-(tert-butyloxycarbonyl)-valine.
Elementaj microanalysis: %oC %>H %N %Cl Calculated: 56.52 6.39 12.68 12.83 Found: 56.63 6.57 12.80 12.62 PHARMACOLOGICAL STUDY QF COMPOUNDS OF THE INVENTION EXAMPLE 76: Inhibition of activated protein C and of coagulation and fibrinolysis serine proteases In order to assess in vitro the inhibitory activity of products of the invention on purified human activated protein C (Diagnostica Stago), the chromogenic substrate pyroGlu-Pro-10 Arg-pNA (0.39mM, S2366, Chromogenix) was added to a given amount of activated protein C (2nM) previously incubated with or without the inhibitor under test (20°C, 30 minutes).
In order to assess in vitro the selectivity with respect to thrombin and plasmin, the same protocol was applied to purified human thrombin (0.7nM, Sigma) and to purified human 15 plasmin (2nM, Stago), using as substrates purified human fibrinogen (6|oM, Enzyme Research Laboratories) and the paracitroanilide peptide <Glu-Phe-Lys-pNA (0.37mM, S2403, Chromogenix), respectively.
The inhibitors, enzymes and substrates are diluted in the same buffer (0.0 ImM phosphate buffer pH 7.4 containing 0.12M sodium chloride and 0.05 % bovine serum albumin in the 20 case of thrombin and 50mM TRIS-HC1 buffer pH 7.4 containing 0.12M sodium chloride, 3mM calcium chloride and 0.05 % bovine serum albumin in the case of activated protein C and plasmin) and then dispensed in a volume of 50 pi onto a polystyrene microplate.

Claims (24)

-48- The paranitroanilide liberated or the fibrin formed by the action of the serine protease is measured spectrophotometrically at 405 nm after reacting for from 10 to 30 minutes at 20°C. In this test the compounds of the invention are powerful inhibitors of activated protein C 5 (the concentration of compounds inhibiting 50 % (IC50) of the enzymatic activity being of the order of from 20 to lOOOnM). The compounds moreover possess very marked selectivity with respect to a fibrinolysis serine protease, plasmin, and a coagulation serine protease, thrombin. By way of example, the compound of Example 1 has an IC50 of 820nM with respect to 10 activated protein C, of 1 lOOnM with respect to plasmin and of >33,000nM with respect to thrombin. EXAMPLE 77: Pharmaceutical composition Formula for the preparation of 1000 tablets each containing 10 mg of active ingredient: compound of Example 1 10 g 15 hydroxypropylcellulose 2g wheat starch 10 g lactose 100 g magnesium stearate 3 g talc 3 g -49- CLAIMS
1. Compound of formula (I): 0 R^N. "5 (i), r/ r, "3 wherein: Ri represents an aryl group, a heteroaryl group or a linear or branched (Ci-C6)alkyl group optionally substituted by one or more identical or different groups selected from aryl and heteroaryl, or Ri represents a group of formula -(CO^CR^RzNRgRg wherein : - Re represents a hydrogen atom or a group selected from aryl, heteroaryl, heterocycloalkyl, (C3-C8)cycloalkyl and linear or branched (Ci-C6)alkyl optionally substituted by one or more identical or different groups selected from aryl, heteroaryl, heterocycloalkyl, (C3-Cg)cycloalkyl and carboxy, - R7 represents a hydrogen atom or a linear or branched (Ci-C6)alkyl group, - or R6 and R7 together form a (C3-Cg)cycloalkyl group, - Rg represents a hydrogen atom or a linear or branched (Ci-C6)alkyl group, - and R9 represents a hydrogen atom or a group R9 wherein R9 represents a group selected from: • linear or branched (Ci-Ce)alkyl optionally substituted by an aryl, carboxy, linear or branched (Ci-C6)alkoxy-carbonyl or carbamoyl group, • aryl, • heteroaryl, • and sulphonyl substituted by a group selected from (C3-Cg)cycloalkyl, heterocycloalkyl, aryl (optionally substituted by an aryloxy or heteroaryloxy group), and linear or branched (Ci-C6)alkyl optionally substituted by an aryl, heteroaryl, (C3-Cg)cycloalkyl or heterocycloalkyl group, -50- 5>l R2 represents a hydrogen atom or a linear or branched (Ci-C6)alkyl group, R3 represents a hydrogen atom or a linear or branched (Ci-C6)alkyl group optionally substituted by one or more aryl groups, R4 represents a saturated or unsaturated, 7- to 15-membered bicyclic system or a linear or branched (Ci-Ce)alkyl group optionally substituted by one or more aryl groups, or R3 and R4, together with the carbon atom carrying them, form a saturated or unsaturated, 3- to 18-membered, mono-, bi- or tri-cyclic system optionally containing one or more hetero atoms selected from O, S and N and optionally substituted by one or more identical or different groups selected from halogen, linear or branched (Ci-C6)alkyl, linear or branched (Ci-C6)alkoxy, hydroxy, linear or branched (Ci-C6)trihaloalkyl, amino (optionally substituted by one or more linear or branched (Ci-C6)alkyl groups) and carboxy, n represents zero, 1 or 2, Ar represents an aryl or heteroaryl group, ^ Rs represents a group selected from amino, guanidino, cyano and amidino optionally substituted by a hydroxy or linear or branched (Ci-C6)alkoxy-carbonyl group, its optical isomers, and also addition salts thereof with a pharmaceutically acceptable acid, a heterocycloalkyl group being understood to mean a 3- to 8-membered, saturated monocyclic group containing one, two or three hetero atoms selected from oxygen, nitrogen and sulphur, it being understood that the heterocycle may optionally be substituted by one or more identical or different groups selected from halogen, linear or branched (Ci-C6)alkyl, linear or branched (Ci-C6)alkoxy, oxo, hydroxy, linear or branched (Ci-C6)trihaloalkyl and amino (optionally substituted by one or more linear or branched (Ci-C6)alkyl groups), -51 - an aryl group being understood to mean phenyl, biphenylyl or naphthyl, each of those groups being optionally substituted by one or more identical or different groups selected from halogen, linear or branched (Ci-C6)alkyl, linear or branched (Ci-C6)alkoxy, hydroxy, linear or branched (Ci-C6)trihaloalkyl, amino (optionally substituted by one or more linear 5 or branched (C i -C6)alkyl -groups) and carboxy, and a heteroaryl group being understood to mean a mono- or bi-cyclic, 5- to 12-membered, aromatic group containing one, two or three hetero atoms selected from oxygen, nitrogen and sulphur, it being understood that the heteroaryl may optionally be substituted by one or more identical or different groups selected from halogen, linear or branched (Ci-C6)alkyl, 10 hydroxy, linear or branched (Ci-Cg)alkoxy, trihalomethyl and amino (optionally substituted by one or more linear or branched (Ci-C6)alkyl groups).
2. Compound of formula (I) according to claim 1, wherein Ri represents a group of formula -(CCO-CHReNHRg wherein R6 represents a (C3-Cg)cycloalkyl group, or linear or branched (Ci-C6)alkyl optionally substituted by a (C3-C8)cycloalkyl group, and R9 15 represents a group selected from linear or branched (Ci-C6)alky1 optionally substituted by a carboxy, linear or branched (Ci-C6)alkoxy-carbonyl or carbamoyl group, and linear or branched (Ci-C6)alkylsulphonyl substituted by a (C3-Cg)cycloalkyl group.
3. Compound of formula (I) according to either claim 1 or claim 2, wherein R3 and R4, which may be the same or different, each represent a linear or branched (Ci-C6)alkyl 20 group.
4. Compound of formula (I) according to either claim 1 or claim 2, wherein R3 and R4 together form an optionally substituted indanyl group or a cyclopentapyridyl group.
5. Compound of formula (I) according to any one of claims 1 to 4, wherein n represents 1. - 52 -
6. Compound of formula (I) according to any one of claims 1 to 5, wherein Ar represents a phenyl group and R5 represents an amidino group optionally substituted by a hydroxy group.
7. Compound of formula (I) according to any one of claims 1 to 5, wherein Ar represents a pyridyl group substituted by a methyl group and R5 represents an amino group.
8. Compound of formula (I) according to claim 1, wherein Ri represents a group of formula -(CO)-CHR^NRgR9 wherein R6, Rs and R9 are as defined for formula (I) and the centre of asymmetry composed of the carbon atom carrying the substituents R6 and NRsRg is of the R configuration.
9. Compound of formula (I) according to claim 1, which is {[(lR)-2-({2-[({4-amidinobenzyl} -amino)-carbonyl] -indan-2-yl} -amino)-1 -cyclohexyl-2-oxoethyl] -amino}acetic acid, its optical isomers, and also addition salts thereof with a pharmaceutically acceptable acid.
10. Compound of formula (I) according to claim 1, which is ethyl {[(lR)-2-({2-[({4-[amino-(hydroxyimino)-methyl]-benzyl}-amino)-carbonyl]-indan-2-yl}-amino)-l-cyclohexyl-2-oxoethyl]-amino}-acetate, its optical isomers, and also addition salts thereof with a pharmaceutically acceptable acid.
11. Compound of formula (I) according to claim 1, which is {[(lR)-2-({2-[({4-amidinobenzyl} -amino)-carbonyl]-indan-2-yl} -amino)-1 -cyclohexylmethyl-2-oxoethyl]-amino}acetic acid, its optical isomers, and also addition salts thereof with a pharmaceutically acceptable acid.
12. Compound of formula (I) according to claim 1, which is {[(lR)-2-({2-[({4-amidinobenzyl} -amino)-carbonyl]-indan-2-yl} -amino)-1 -isopropyl-2-oxoethyl]-amino} acetic acid, its optical isomers, and also addition salts thereof with a pharmaceutically acceptable acid. INTELLEC "ERTY OFFICE 06 OCT 2005 received -53-
13. Compound of formula (I) according to claim 1, which is N-(4-amidinobenzyl)-2-[((2R)-2-cyclohexyl-2- {[(cyclohexylmethyl)-sulphonyl] -amino } -ethanoyl)-amino] -2-indancarboxamide, its optical isomers, and also addition salts thereof with a pharmaceutically acceptable acid.
14. Compound of formula (I) according to claim 1, which is N-(4-amidinobenzyl)-2-[((2R)-2- {[(cyclohexylmethyl)-sulphonyl] -amino} -3 -methylbutanoyl)-amino] -2-indan-carboxamide, its optical isomers, and also addition salts thereof with a pharmaceutically acceptable acid.
15. Compound of formula (I) according to claim 1, which is N-(4-amidinobenzyl)-2-[((2R)-2-{[isobutylsulphonyl]-amino}-3-methylbutanoyl)-amino]-2-indancarboxamide, its optical isomers, and also addition salts thereof with a pharmaceutically acceptable acid.
16. Compound of formula (I) according to claim 1, which is N-(4-amidinobenzyl)-6-[((2R)-2- {[(cyclohexylmethyl)-sulphonyl] -amino} -3 -methylbutanoyl)-amino] -6,7-dihydro-5i/-cyclopenta[b]pyridine-6-carboxamide, its optical isomers, and also addition salts thereof with a pharmaceutically acceptable acid.
17. Process for the preparation of compounds of formula (I) according to claim 1, characterised in that a compound of formula (II): wherein R3 and R4 are as defined for formula (I) and Pi represents a protecting group for the amino function, (ii), r3 r4 is reacted, under peptide coupling conditions, with a compound of formula (III): H2N^(CH2)n~Ar-R'5 (HI), -54- wherein n and Ar are as defined for formula (I) and R5 represents a group selected from amino, guanidino and amidino optionally substituted by a hydroxy or linear or branched (Ci-C6)alkoxy-carbonyl group, to yield, after deprotection, the compound of formula (IV): O ar r'5 (IV), r3 R4 wherein R3, R4, n, Ar and R'5 are as defined hereinbefore, which is reacted: • either, when it is desired to obtain compounds of formula (I) wherein Ri represents an aryl group, a heteroaryl group or a linear or branched (Ci-C6)alkyl group which is 10 optionally substituted, with a compound of formula (V): Ria-Z (V), wherein Ria represents an aryl group, a heteroaryl group or a linear or branched (Ci-C6)alkyl group optionally substituted by one or more groups selected from aryl and heteroaryl, and Z represents a leaving group such as, for example, a halogen atom 15 or a tosylate, mesylate or triflate group, to yield, after optional deprotection, the compounds of formula (la), a particular case of the compounds of formula (I): O RuR2N\Jv NH Ar R5 (la), r3/ R4 wherein Ria, R2, R3, Rt, n, Ar and R5 are as defined hereinbefore, 20 • or, when it is desired to obtain compounds of formula (I) wherein Ri represents an optionally substituted, linear or branched (C2-C6)alkyl group, with a compound of formula (VI), under reductive amination conditions : Rlb-CHO (VI), -55- wherein Rib represents a linear or branched (Ci-C5)alkyl group optionally substituted by one or more groups selected from aryl and heteroaryl, to yield, after optional deprotection, the compounds of formula (lb), a particular case of the compounds of formula (I): O R lb*;r37 R4;wherein Rib, R2, R3, R4, n, Ar and R5 are as defined hereinbefore,;• or, when it is desired to obtain compounds of formula (I) wherein Ri represents a group of formula -(CCty-CRsRvNRgRs), wherein R& R7, Rg and R9 are as defined for formula (I), with a compound of formula (VII), under peptide coupling conditions :;wherein R$ and R7 are as defined for formula (I) and P2 represents a protecting group for the amino function, to yield, after deprotection, the compound of formula (VIII):;15 which is reacted, if desired, with a compound of formula (IX) :;R'9-Z (IX),;wherein R'9 is as defined for formula (I) and Z represents a leaving group such as, for example, a halogen atom or a tosylate, mesylate or triflate group,;to yield the compound of formula (X):;-56-;o;R,,HN ¥ X ^nh"(CH2>"^a'-r,5 to,;O R( R4;wherein R'9, R$, r7, r2, r3, r4, n, Ar and R'5 are as defined hereinbefore,;which compounds of formula (VIII) or (X) are reacted, if desired, with a compound of formula (XI):;5 R'g-Z (XI),;wherein R'g represents a linear or branched (Ci-C6)alkyl group and Z represents a leaving group such as, for example, a halogen atom or a tosylate, mesylate or triflate group,;to yield the compound of formula (XII):;XCH2)„;RW* Y X^NH Ar R'5 (XII), O R3 R4 10 wherein R'g, R6, r7, R2, r3, R4, n, Ar and R5 are as defined hereinbefore and R9 is as defined for formula (I), which compounds of formula (VIII), (X) or (XII) are optionally deprotected to yield the compound of formula (Ic), a particular case of the compounds of formula (I): V -R- 0 -(CH2) NH Ar R5 (Ic), 0 R37 R4 RgR^N 15 wherein Rg, R9, R6, R7, R2, r3, r4, n, Ar and R5 are as defined hereinbefore the compounds of formulae (la), (lb) and (Ic) constituting the totality of the compounds of formula (I), which are purified, if necessary, according to a conventional purification technique, are separated, if desired, into their isomers according to a conventional separation technique and are converted, if desired, into their addition salts with a 20 pharmaceutically acceptable acid. -57-
18. Pharmaceutical composition comprising as active ingredient a compound according to any one of claims 1 to 16, in combination with one or more inert, non-toxic and pharmaceutically acceptable carriers.
19. Pharmaceutical composition according to claim 18, for use as a medicament in the 5 treatment of any pathological condition involving activated protein C.
20. Pharmaceutical composition according to claim 19, for use as a medicament in the treatment of disorders involving a dysfunction of haemostasis requiring procoagulant treatment, including all haemorrhagic clinical situations such as von Willebrand's disease or haemophilia A or B. 10
21. Pharmaceutical composition according to claim 19, for use as an antidote medicament in antithrombotic treatments such as anticoagulant, antiplatelet and fibrinolytic treatments.
22. A compound as claimed in claim 1 substantially as herein described with reference to any example thereof.
23. A process as claimed in claim 17 substantially as herein described with reference to any example thereof.
24. A pharmaceutical composition as claimed in claim 18 substantially as herein described with reference to any example thereof. INTELLECTUAL PfOPERTY OFFICE 0FN.Z. 20 sep 2005 received
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